Abstract

Atypical hemolytic-uremic syndrome (aHUS; OMIM 235400) is genetically and clinically heterogeneous. Mutations in membrane cofactor protein (MCP; CD46), a widely expressed complement regulator, predispose to recurrent forms of the disease. Patients carrying MCP mutations have a favorable clinical outcome in comparison to those with factor H (CFH) or factor I (IF) mutations, which lead in most cases to end-stage renal failure. We identified 1 patient who presented at 1 year of age with a first episode of aHUS requiring dialysis therapy. After 2 recurrences of the disease, the patient developed end-stage renal failure. No mutation in the CFH and IF genes was found. A novel homozygous mutation (IVS10+2 T-->C) in the splice-donor of exon 10 encoding the transmembrane region of the MCP gene was associated with dramatically decreased cell-surface expression of MCP. Because the nucleotide substitution was inherited from the patient's father, but not her mother, a large deletion or uniparental disomy was suspected. Both karyotyping and cytogenetic analysis of chromosome 1q32 were performed, for which MCP maps showed no abnormalities. Subsequent genotype analysis using microsatellite markers spanning chromosome 1 showed that the affected child was homozygous for the entire series of markers tested and that all alleles originated from the father. Complete paternal uniparental isodisomy of chromosome 1 is a novel mechanism resulting in severe deficiency of MCP expression. The outcome of the disease reported here indicates that MCP mutation and complete paternal uniparental disomy of chromosome 1 could have an additive effect in determining the severity of the HUS phenotype.